PB2079: LACTATE DECREASES BORTEZOMIB SENSITIVITY AND PREDICTS POOR CLINICAL OUTCOMES OF MULTIPLE MYELOMA
Authors: Naya MA, Qiong LI, Xinlei LI, Yunjing Zeng, Dezhi Huang, Jing Xia, Bangdong Liu, Jun Rao, XI Zhang
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Multiple myeloma (MM) is an incurable hematological malignancy of monoclonal proliferation of plasma cells in the bone marrow. According to NCCN guidelines, the Durie-Salmon Staging System (DS staging) and International Staging System (ISS staging) were used for prognostic assessment and risk stratification of MM. However, this risk system also has limited accuracy in survival prediction and assigns a large fraction of the patients to an intermediate-risk group whose outcomes are largely uncertain. Proteasome inhibitor (bortezomib) is the backbone of patients’ standard therapy with a higher response ratio and prolonged survival. However, some patients will ultimately relapse and progress. Metabolism reprogramming is now recognized as a hallmark of cancer. Lactate, a metabolite of the glycolytic pathway, was associated with the severity of critical illness and participated in the tumorigenesis and development of tumors. In hematological malignancies, lactate acidosis indicates an inferior clinical prognosis for lymphoma and myeloma. However, there was no specific research on lactate utilized as a biomarker, promoting myeloma evolution and resistance to chemotherapy, and its mechanisms in multiple myeloma. Aims: To explore the role and clinical significance of lactate as a biomarker in MM, and to investigate the function and mechanism of Lac in promoting the proliferation and reducing the sensitivity of BTZ in MM. Methods: Take targeted energy metabonomics to explore differences in metabolism substances in peripheral blood and bone marrow in MM. Expanding peripheral blood samples validated the elevated lactate in MM, investigated the correlation of lactate with clinical characteristics, and assessed the value of lactate as a biomarker of multiple myeloma. The myeloma cells were cultured in vitro and utilized CCK-8 to detect cell viability after being treated with Lac in different concentrations and times. Applied BTZ or combined Lac to treat with cells, explored apoptosis and cell cycle changes by flow cytometry, and detected the apoptosis and cycle-related proteins changes by Western blot. After applying BTZ or combined Lac to treat with cells, use western blot to detect the changes in the NF-kappa B pathway proteins. Results: Targeted energy metabolomics showed MM’s cyclic AMP, lactate, α-ketoglutarate, glucose-6-phosphate, and malic acid were significantly increased compared with control subjects. Lactate of the peripheral blood in MM is significantly higher than in normal subjects. The lactate was positively correlated with the DS stage, ISS stage, and the ratio of involved/unaffected free light chains in hematuria. Overmore, the patients with more elevated lactate have unsatisfactory responses. Vitro proliferation, apoptosis, and cell cycle in myeloma cells showed that lower dose Lac could promote the proliferation and the transformation of cell cycle G0/G1 to S, but not affect the apoptosis. Western blot results also confirmed the corresponding changes in cell cycle-related proteins. The combined Lac decreased the sensitivity of BTZ and antagonized the BTZ-induced apoptosis and G2/M cycle arrest in cells. BTZ decreased the protein levels of NFKB2 and RelB, while Lac increased them. The combined Lac could partially recover the reduction in NFKB2 and RelB protein caused by BTZ. Summary/Conclusion: Metabolic changes are important for MM tumor cell proliferation and treatment response. Lactate could be used as a biomarker for MM and as a therapeutic target to overcome the chemotherapy resistance of BTZ.Keywords: Multiple myeloma, Drug resistance, Bortezomib